This application is highly responsive to the major goal of the RFA (AI-18-017) to support the development of next-generation biologics with immune-modulating effects that may lead to long-lasting HIV remission. Functional cure of HIV infection has been stymied by the inability of the immune system of HIV-infected individuals to eliminate effectively latently infected cells following reactivation, resulting in the recurrence of viremia after stopping antiretroviral therapy. We propose to exploit our increasing understanding of the precise signals and molecules that mobilize potent T cell responses and sophisticated protein design and engineering principles to construct novel immunostimulatory biologics consisting of highly stable dimeric IgG Fc-fusion proteins, termed synTacs. These biologics mimic APC functions by MHC-mediated presentation of defined peptides to TCRs with delivery of costimulatory and/or cytokine signals. The key element of the synTac architecture is the use of a single chain MHC molecule, covalently linked to a defined HIV-derived peptide as a targeting module that triggers the primary TCR activation signal. In parallel, the synTac delivers covalently linked costimulatory ligands or cytokines to the targeted HIV-specific CD8+ T cells to provide a costimulatory signal to activate fully the T cells or a cytokine signal to drive T cell proliferation and/or differentiation. We have validated this approach by constructing synTacs which target the HLA-A*0201-restricted HIV Gag epitope, SL9, linked to the costimulatory ?-CD28 or 4-1BBL molecules that specifically activated and expanded primary SL9-specific CD8+ T cells from HIV-infected individuals. We propose to develop HIV-specific synTacs and identify the optimal costimulatory and/or cytokine signals to enable them to function as targeted biologics capable of stimulating, expanding and differentiating selectively patient-derived HIV-specific CD8+ T cells with the most potent capacity to eliminate HIV-infected T cells. We will determine the in vivo capacity of synTac biologics to activate, expand and differentiate HIV-specific CD8+ T cells capable of preventing recurrent viremia by eliminating reactivated latently infected cells using a novel humanized mouse model we have developed. As an alternative approach, we also propose to harness the potential potency of HIV-specific CAR- T cells, which recognize antigen with recombinant immunoreceptors such as scFv rather than MHC-restricted TCRs, by developing an alternative biologic, synTac-like molecules that bind to the CAR-T immunoreceptor to deliver the optimal costimulatory and/or cytokine signals to amplify HIV-specific CAR-T cell in vivo function.